Abstract
BackgroundWhile human gut microbiomes vary significantly in taxonomic composition, biological pathway abundance is surprisingly invariable across hosts. We hypothesized that healthy microbiomes appear functionally redundant due to factors that obscure differences in gene abundance between individuals.ResultsTo account for these biases, we developed a powerful test of gene variability called CCoDA, which is applicable to shotgun metagenomes from any environment and can integrate data from multiple studies. Our analysis of healthy human fecal metagenomes from three separate cohorts revealed thousands of genes whose abundance differs significantly and consistently between people, including glycolytic enzymes, lipopolysaccharide biosynthetic genes, and secretion systems. Even housekeeping pathways contain a mix of variable and invariable genes, though most highly conserved genes are significantly invariable. Variable genes tend to be associated with Proteobacteria, as opposed to taxa used to define enterotypes or the dominant phyla Bacteroidetes and Firmicutes.ConclusionsThese results establish limits on functional redundancy and predict specific genes and taxa that may explain physiological differences between gut microbiomes.
Highlights
While human gut microbiomes vary significantly in taxonomic composition, biological pathway abundance is surprisingly invariable across hosts
To describe variation within healthy gut microbiota across different human populations, we randomly selected 123 metagenomes of healthy individuals from the Human Microbiome Project (HMP, n = 42) [13], controls in a study of type II diabetes (T2D, n = 44) [33], and controls in a study of glucose control (GC, n = 37) [34]. These span American, Chinese, and European populations, respectively. We mapped these metagenomes to Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology (KO) families with ShotMAP [35] and counted reads for 17,417 gene families
We quantified gene family abundance using reads per kilobase of genome equivalents (RPKG) [36]. This method of calculating abundances takes into account differences in the average genome size within different metagenomes, as well as factors such as gene length, that can bias counts
Summary
While human gut microbiomes vary significantly in taxonomic composition, biological pathway abundance is surprisingly invariable across hosts. We hypothesized that healthy microbiomes appear functionally redundant due to factors that obscure differences in gene abundance between individuals. The microbes that inhabit the mammalian gut encode a wealth of proteins that contribute to a broad range of biological functions, from modulating the immune system [1,2,3] to participating in metabolism [4, 5]. Shotgun metagenomics is revolutionizing our ability to identify protein-coding genes from these microbes and associate gene levels with disease [6], drug efficacy [7] or sideeffects [8], and other host traits. The functional capabilities of the human gut microbiome go beyond statistical associations. Examples include the colitis-inducing cytolethal distending toxins of Helicobacter hepaticus [10] and the enzymes of commensal bacteria that protect against these toxins by producing anti-inflammatory polysaccharide A [11]
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